This invention relates to a process for preparing various 4-(hydroxymethyl)-imidazoles, and, particularly, their hydrochlorides. These compounds are intermediates for preparing commercially important medicinal agents having histamine H.sub.2 -agonist activity of which the inhibition of gastric secretion is one medical indication (see Black et al, Nature, 1972, 236-385). An example of one of these end products is cimetidine, N-cyano-N'-methyl-N"-[5-methyl-4-imidazolyl-(methylthio)-ethyl]-guanidine, U.S. Pat. No. 3,950,333.
In U.S. Pat. No. 3,984,293, there is described the state of the art as background to the electrochemical reduction of 4-imidazole carboxylic acids. That invention is useful, however, it necessitates an extra chemical step prior to reduction, namely, hydrolysis of the ester intermediate to form the free carboxylic acid. Also, U.S. Pat. No. 4,055,573 teaches a method for preparing 4-(hydroxymethyl)-imidazoles and their lower alkyl ethers by electrochemical reduction in concentrated sulfuric acid in concentrated solutions using standard electrochemical cells with yields up to 80%. It should be noted that, although the imidazole alcohol is produced, an equally important product is imidazole ethyl ether. Subsequent reaction of the mixed alcoholalkyl ether with cysteamine hydrochloride produces the thioamine in about 60% yield. Further, in British Pat. No. 1,341,376 the reduction of 4-methyl-5-carbethoxyimidazole with lithium aluminum hydride, followed by addition of water, filtration and acidification with hydrochloric acid, affords 4-methyl-5-hydroxymethylimidazole hydrochloride. Although the yield is not given, it appears to amount to about 60%. Subsequent reactions produced 4-methyl-5-(2-aminoethyl)-imidazole.
In the production of 4-(hydroxymethyl)-imidazole hydrochloride, it is always an objective to minimize the production of by-products because they represent yield losses and impurities which are more preferably avoided for economic, purification and governmental regulatory reasons. However, several processes for making such 4-(hydroxymethyl)-imidazoles can produce substantial quantities of imidazole ethers. Such ethers can also be produced by heating 4-(hydroxymethyl)-imidazole compounds at temperatures from about 40 to about 60.degree. C. for periods of time ranging from 2 to about 3 hours. Further, such compounds are not formed in as great an amount at lower temperatures. Accordingly, processes which can remove or purify the 4-(hydroxymethyl)-imidazoles of such imidazole ester compounds are useful and desirable.